Combination of regorafenib and acetylsalicylic acid for treating cancer

ABSTRACT

The present invention relates to pharmaceutical compositions and combinations comprising regorafenib and acetylsalicylic acid, or a hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof or a polymorph thereof for treating, preventing or managing diseases and conditions including hyperproliverative disorders such as cancer in humans and other mammals.

The present invention relates to pharmaceutical compositions andcombinations comprising regorafenib and acetylsalicylic acid, or ahydrate, solvate, metabolite or pharmaceutically acceptable salt thereofor a polymorph thereof for treating, preventing or managing diseases andconditions including hyperproliverative disorders such as cancer inhumans and other mammals.

Regorafenib which is4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-3-fluorophenoxy}-pyridine-2-carboxylicacid methylamide, a compound of formula (I)

is a potent anti-cancer and anti-angiogenic agent that possesses variousactivities including inhibitory activity on the VEGFR, PDGFR, raf, p38,and/or flt-3 kinase signalling molecules and it can be used in treatingvarious diseases and conditions like hyper-proliferative disorders suchas cancers, tumors, lymphomas, sarcomas and leukemias as described in WO2005/009961. It is currently developed for the treatment of colorectalcancer and gastrointestinal stromal tumors. Furthermore salts of thecompound of formula (I) such as its hydrochloride, mesylate andphenylsulfonate are mentioned in WO 2005/009961. The monohydrate of thecompound of formula (I) is mentioned in WO 2008/043446. An improvedprocess for the manufacturing of regorafenib in high purity is describedin WO 2011/128261.

Acetylsalicylic acid is a well-known drug which cannot only be used fortreating pain or reducing the risk to develop a cardiovascular event ordisease but there are also hints for reducing the risk of developingcancer diseases (Rothwell P M et al (2012) Short-term effects of dailyacetylsalicylic acid on cancer incidence, mortality and non-vasculardeath: analysis of the time course of risks and benefits in 51randomized controlled trials. Lancet. 379: 1602-1612).

Furthermore acetylsalicylic acid can reduce metastasis of tumorseffecting a reduction of mortality in particular in patients withcolorectal cancer (Rothwell P M et al (2012) Effect of dailyacetylsalicylic acid on risk of cancer metastasis: a study of incidentcancers during randomised controlled trials. Lancet. 379: 1591-1601).

Object of the present invention is the improvement of the cancer therapyby the administration of regorafenib and acetylsalicylic acid incombination.

Surprisingly the combination of regorafenib and acetylsalicylic acidshows a significant efficacy improvement over the sum of themonotherapies. Furthermore the profile of the side effects (e.g.hand-foot syndrome, elevated blood pressure, fatigue, diarrhea andmucosal inflammation) can be improved.

The present invention pertains to a combination comprising regorafenibwhich is the compound of the formula (I)

and acetylsalicylic acid, or a hydrate, solvate, metabolite orpharmaceutically acceptable salt of thereof, or a polymorph thereof.

The term “the compound of formula (I)” or “regorafenib” refer to4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]-3-fluorophenoxy}-N-methylpyridine-2-carboxamideas depicted in formula (I).

Solvates for the purposes of the invention are those forms of thecompounds or their salts where solvent molecules form a stoichiometriccomplex in the solid state and include, but are not limited to forexample water, ethanol and methanol.

Hydrates are a specific form of solvates, where the solvent molecule iswater. Hydrates of the compounds of the invention or their salts arestoichiometric compositions of the compounds or salts with water, suchas, for example, hemi-, mono- or dihydrates. Preference is given to themonohydrate of regorafenib.

Salts for the purposes of the present invention are preferablypharmaceutically acceptable salts of the compounds according to theinvention. Suitable pharmaceutically acceptable salts are well known tothose skilled in the art and include salts of inorganic and organicacids, such as hydrochloric acid, hydrobromic acid, sulfuric acid,phosphoric acid, methanesulphonic acid, trifluoromethanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid (tosylate salt),1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, acetic acid,trifluoroacetic acid, malic acid, tartaric acid, citric acid, lacticacid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoicacid, salicylic acid, phenylacetic acid, and mandelic acid. In addition,pharmaceutically acceptable salts include salts of inorganic bases, suchas salts containing alkaline cations (e.g., Li⁺ Na⁺ or K⁺), alkalineearth cations (e.g., Mg⁺², Ca⁺² or Ba⁺²), the ammonium cation, as wellas acid salts of organic bases, including aliphatic and aromaticsubstituted ammonium, and quaternary ammonium cations, such as thosearising from protonation or peralkylation of triethylamine,N,N-diethylamine, N,N-dicyclohexylamine, lysine, pyridine,N,N-dimethylaminopyridine (DMAP), 1,4-diazabiclo[2.2.2]octane (DABCO),1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Preference is given to thehydrochloride, mesylate or phenylsulfonate salt of regorafenib.

Metabolites of regorafenib for the purpose of the present inventioninclude4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide1-oxide,4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-(hydroxymethyl)pyridine-2-carboxamide,4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]pyridine-2-carboxamideand4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]pyridine-2-carboxamide1-oxide.

Preferred are regorafenib and the monohydrate of regorafenib as acompound of the present invention.

The compounds of the invention may be prepared by use of known chemicalreactions and procedures.

Method for Treatment:

The present invention also relates to a method for using the combinationand compositions thereof, to treat mammalian hyper-proliferativedisorders. This method comprises administering to a mammal in needthereof, including a human, an amount of the combination, which iseffective to treat the disorder. Hyper-proliferative disorders includebut are not limited to solid tumors, such as cancers of the breast,respiratory tract, brain, reproductive organs, digestive tract, urinarytract, eye, liver, skin, head and neck, thyroid, parathyroid and theirdistant metastases. Those disorders also include lymphomas, sarcomas,and leukemias.

Examples of breast cancer include, but are not limited to invasiveductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ,and lobular carcinoma in situ.

Examples of cancers of the respiratory tract include, but are notlimited to small-cell and non-small-cell lung carcinoma, as well asbronchial adenoma and pleuropulmonary blastoma.

Examples of brain cancers include, but are not limited to brain stem andhypophtalmic glioma, cerebellar and cerebral astrocytoma,medulloblastoma, ependymoma, as well as neuroectodermal and pinealtumor.

Tumors of the male reproductive organs include, but are not limited toprostate and testicular cancer. Tumors of the female reproductive organsinclude, but are not limited to endometrial, cervical, ovarian, vaginal,and vulvar cancer, as well as sarcoma of the uterus.

Tumors of the digestive tract include, but are not limited to anal,colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal,small intestine, and salivary gland cancers.

Preference is given to colorectal cancer.

Preference is also given to gastrointestinal stromal tumors (GIST).

Tumors of the urinary tract include, but are not limited to bladder,penile, kidney, renal pelvis, ureter, and urethral cancers.

Eye cancers include, but are not limited to intraocular melanoma andretinoblastoma.

Examples of liver cancers include, but are not limited to hepatocellularcarcinoma (liver cell carcinomas with or without fibrolamellar variant),cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixedhepatocellular cholangiocarcinoma.

Preference is given to hepatic cell cancer.

Skin cancers include, but are not limited to squamous cell carcinoma,Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, andnon-melanoma skin cancer.

Head-and-neck cancers include, but are not limited tolaryngeal/hypopharyngeal/nasopharyngeal/oropharyngeal cancer, and lipand oral cavity cancer.

Lymphomas include, but are not limited to AIDS-related lymphoma,non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Hodgkin's disease,and lymphoma of the central nervous system.

Sarcomas include, but are not limited to sarcoma of the soft tissue,osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, andrhabdomyosarcoma.

Leukemias include, but are not limited to acute myeloid leukemia, acutelymphoblastic leukemia, chronic lymphocytic leukemia, chronicmyelogenous leukemia, and hairy cell leukemia.

These disorders have been well characterized in humans, but also existwith a similar etiology in other mammals, and can be treated byadministering pharmaceutical compositions of the present invention.

Based upon standard laboratory techniques known to evaluate compoundsuseful for the treatment of hyper-proliferative disorders, by standardtoxicity tests and by standard pharmacological assays for thedetermination of treatment of the conditions identified above inmammals, and by comparison of these results with the results of knownmedicaments that are used to treat these conditions, the effectivedosage of the compounds of this invention can readily be determined fortreatment of each desired indication. The amount of the activeingredient to be administered in the treatment of one of theseconditions can vary widely according to such considerations as theparticular compound and dosage unit employed, the mode ofadministration, the period of treatment, the age and sex of the patienttreated, and the nature and extent of the condition treated.

The present invention further provides the use of the compound of theinvention for the preparation of a pharmaceutical compositions for thetreatment of the aforesaid disorders.

Administration

Combinations of the present invention can be administered in any form byany effective route, including, e.g., oral, parenteral, enteral,intravenous, intraperitoneal, topical, transdermal (e.g., using anystandard patch), ophthalmic, nasally, local, non-oral, such as aerosal,inhalation, subcutaneous, intramuscular, buccal, sublingual, rectal,vaginal, intra-arterial, and intrathecal, etc. They can be administeredalone, or in combination with any ingredient(s), active or inactive.

Preference is given to an oral administration.

Alternatively acetylsalicylic acid can be administered intravenously.

Combinations of the present invention can be converted in a known mannerinto the usual formulations, which may be liquid or solid formulationse.g. without limitation normal and enteric coated tablets, capsules,pills, powders, granules, elixirs, tinctures, solution, suspensions,syrups, solid and liquid aerosols and emulsions.

Examples of solid formulations for oral administration are described inU.S. provisional application No. 60/605,752.

Generally, the use of the combinations of the present inventionmentioned before will serve to:

(1) yield better efficacy in reducing the growth of a tumor or eveneliminate the tumor as compared to administration of either agent alone,

(2) provide for the administration of lesser amounts of the administeredchemotherapeutic agents,

(3) provide for a chemotherapeutic treatment that is well tolerated inthe patient with fewer deleterious pharmacological complications thanobserved with single agent chemotherapies and certain other combinedtherapies,

(4) provide for treating a broader spectrum of different cancer types inmammals, especially humans,

(5) provide for a higher response rate among treated patients,

(6) provide for a longer survival time among treated patients comparedto standard chemotherapy treatments,

(7) provide a longer time for tumor progression, and/or

(8) yield efficacy and tolerability results at least as good as those ofthe agents used alone, compared to known instances where other canceragent combinations produce antagonistic effects,

“Combination” means for the purposes of the invention not only a dosageform which contains all the components (so-called fixed combinations),and combination packs containing the components separate from oneanother, but also components which are administered simultaneously orsequentially, as long as they are employed for the prophylaxis ortreatment of the same disease.

The amount of the administered active ingredient can vary widelyaccording to such considerations as the particular compound and dosageunit employed, the mode and time of administration, the period oftreatment, the age, sex, and general condition of the patient treated,the nature and extent of the condition treated, the rate of drugmetabolism and excretion, the potential drug combinations and drug-druginteractions, and the like.

An aspect of the invention of particular interest is a combinationcomprising regorafenib in an amount of 4 to 400 mg, preferably from 10to 200 mg, more preferably from 10 to 100 mg.

A further aspect of the invention of particular interest is acombination comprising acetylsalicylic acid in an amount of 50 to 100mg, preferably from 60 to 500 mg, more preferably from 70 to 350 mg.Typical doses of acetylsalicylic acid are 78 mg, 81 mg, 100 mg, 325 mg,500 mg and 1000 mg.

The daily dose of regorafenib is from 10 to 1000 mg, preferably 40 to500 mg, more preferably 80 to 320 mg, e.g. 160 mg.

The daily dose of acetylsalicylic acid is from 50 to 1000 mg, preferablyfrom 60 to 500 mg, more preferably from 70 to 350 mg. Typical dailydoses of acetylsalicylic acid are 78 mg, 81 mg, 100 mg, 325 mg, 500 mgand 1000 mg.

The pharmaceutical composition according to the invention isadministered one or more, preferably up to three, more preferably up totwo times per day. Preference is given to an administration via the oralroute. With each administration the number of tablets or capsules takenin at the same time should not exceed two.

Nevertheless, it may in some cases be advantageous to deviate from theamounts specified, depending on body weight, individual behaviour towardthe active ingredient, type of preparation and time or interval overwhich the administration is affected. For instance, less than theaforementioned minimum amounts may be sufficient in some cases, whilethe upper limit specified has to be exceeded in other cases. In the caseof administration of relatively large amounts, it may be advisable todivide these into several individual doses over the day.

Examples of an administration scheme are as follows: In the first cycledaily doses of 160 mg regorafenib and 81 mg acetylsalicylic acid areadministered for 3 weeks. In week four only 81 mg acetylsalicylic acidare administered. Then the cycle can be repeated. Alternatively thedaily dose of acetylsalicylic acid can be equal or less than 325 mg(e.g. 100 mg) or it can be more than 325 mg (e.g. 500 mg).

The combination can comprise effective amounts of the compound ofFormula I and acetylsalicylic acid, which achieves a greater therapeuticefficacy than when either compound is used alone.

The relative ratios of each compound in the combination can also beselected based on their respective mechanisms of action and the diseasebiology. The relative ratios of each compound can vary widely.

The release of one or more agents of the combination can also becontrolled, where appropriate, to provide the desired therapeuticactivity when in a single dosage form, combination pack, kit or when inseparate independent dosage forms.

The present invention includes pharmaceutical compositions which arecomprised of a pharmaceutically acceptable carrier and apharmaceutically effective amount of the compounds of the presentinvention. A pharmaceutically acceptable carrier is any carrier which isrelatively non-toxic and innocuous to a patient at concentrationsconsistent with effective activity of the active ingredient so that anyside effects ascribable to the carrier do not vitiate the beneficialeffects of the active ingredient. A pharmaceutically effective amount ofcompound is that amount which produces a result or exerts an influenceon the particular condition being treated.

For oral administration, the compounds can be formulated into solid orliquid preparations such as solid dispersion, capsules, pills, tablets,troches, lozenges, melts, powders, solutions, suspensions, or emulsions,and may be prepared according to methods known to the art for themanufacture of pharmaceutical compositions. The solid unit dosage formscan be a capsule which can be of the ordinary hard- or soft-shelledgelatin type containing, for example, surfactants, lubricants, and inertfillers such as lactose, sucrose, calcium phosphate, and corn starch.

In another embodiment, the compounds of this invention may be tabletedwith conventional tablet bases such as lactose, sucrose and cornstarchin combination with binders such as acacia, corn starch or gelatin,disintegrating agents intended to assist the break-up and dissolution ofthe tablet following administration such as potato starch, alginic acid,corn starch, and guar gum, gum tragacanth, acacia, lubricants intendedto improve the flow of tablet granulation and to prevent the adhesion oftablet material to the surfaces of the tablet dies and punches, forexample talc, stearic acid, or magnesium, calcium or zinc stearate,dyes, coloring agents, and flavoring agents such as peppermint, oil ofwintergreen, or cherry flavoring, intended to enhance the aestheticqualities of the tablets and make them more acceptable to the patient.Suitable excipients for use in oral liquid dosage forms includedicalcium phosphate and diluents such as water and alcohols, forexample, ethanol, benzyl alcohol, and polyethylene alcohols, either withor without the addition of a pharmaceutically acceptable surfactant,suspending agent or emulsifying agent. Various other materials may bepresent as coatings or to otherwise modify the physical form of thedosage unit. For instance tablets, pills or capsules may be coated withshellac, sugar or both.

Dispersible powders and granules are suitable for the preparation of anaqueous suspension. They provide the active ingredient in admixture witha dispersing or wetting agent, a suspending agent and one or morepreservatives. Suitable dispersing or wetting agents and suspendingagents are exemplified by those already mentioned above. Additionalexcipients, for example those sweetening, flavoring and coloring agentsdescribed above, may also be present.

The pharmaceutical compositions of this invention may also be in theform of oil-in-water emulsions. The oily phase may be a vegetable oilsuch as liquid paraffin or a mixture of vegetable oils. Suitableemulsifying agents may be (1) naturally occurring gums such as gumacacia and gum tragacanth, (2) naturally occurring phosphatides such assoy bean and lecithin, (3) esters or partial esters derived form fattyacids and hexitol anhydrides, for example, sorbitan monooleate, (4)condensation products of said partial esters with ethylene oxide, forexample, polyoxyethylene sorbitan monooleate. The emulsions may alsocontain sweetening and flavoring agents.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil such as, for example, arachis oil, olive oil, sesameoil or coconut oil, or in a mineral oil such as liquid paraffin. Theoily suspensions may contain a thickening agent such as, for example,beeswax, hard paraffin, or cetyl alcohol. The suspensions may alsocontain one or more preservatives, for example, ethyl or n-propylp-hydroxybenzoate; one or more coloring agents; one or more flavoringagents; and one or more sweetening agents such as sucrose or saccharin.

Syrups and elixirs may be formulated with sweetening agents such as, forexample, glycerol, propylene glycol, sorbitol or sucrose. Suchformulations may also contain a demulcent, and preservative, such asmethyl and propyl parabens and flavoring and coloring agents.

The compounds of this invention may also be administered parenterally,that is, subcutaneously, intravenously, intraocularly, intrasynovially,intramuscularly, or interperitoneally, as injectable dosages of thecompound in a physiologically acceptable diluent with a pharmaceuticalcarrier which can be a sterile liquid or mixture of liquids such aswater, saline, aqueous dextrose and related sugar solutions, an alcoholsuch as ethanol, isopropanol, or hexadecyl alcohol, glycols such aspropylene glycol or polyethylene glycol, glycerol ketals such as2,2-dimethyl-1,1-dioxolane-4-methanol, ethers such as poly(ethyleneglycol) 400, an oil, a fatty acid, a fatty acid ester or, a fatty acidglyceride, or an acetylated fatty acid glyceride, with or without theaddition of a pharmaceutically acceptable surfactant such as a soap or adetergent, suspending agent such as pectin, carbomers, methycellulose,hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifyingagent and other pharmaceutical adjuvants.

Illustrative of oils which can be used in the parenteral formulations ofthis invention are those of petroleum, animal, vegetable, or syntheticorigin, for example, peanut oil, soybean oil, sesame oil, cottonseedoil, corn oil, olive oil, petrolatum and mineral oil. Suitable fattyacids include oleic acid, stearic acid, isostearic acid and myristicacid. Suitable fatty acid esters are, for example, ethyl oleate andisopropyl myristate. Suitable soaps include fatty acid alkali metal,ammonium, and triethanolamine salts and suitable detergents includecationic detergents, for example dimethyl dialkyl ammonium halides,alkyl pyridinium halides, and alkylamine acetates; anionic detergents,for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether,and monoglyceride sulfates, and sulfosuccinates; non-ionic detergents,for example, fatty amine oxides, fatty acid alkanolamides, andpoly(oxyethylene-oxypropylene)s or ethylene oxide or propylene oxidecopolymers; and amphoteric detergents, for example,alkyl-beta-aminopropionates, and 2-alkylimidazoline quarternary ammoniumsalts, as well as mixtures.

The parenteral compositions of this invention will typically containfrom about 0.5% to about 25% by weight of the active ingredient insolution. Preservatives and buffers may also be used advantageously. Inorder to minimize or eliminate irritation at the site of injection, suchcompositions may contain anon-ionic surfactant having ahydrophile-lipophile balance (HLB) of from about 12 to about 17. Thequantity of surfactant in such formulation ranges from about 5% to about15% by weight. The surfactant can be a single component having the aboveHLB or can be a mixture of two or more components having the desiredHLB.

Illustrative of surfactants used in parenteral formulations are theclass of polyethylene sorbitan fatty acid esters, for example, sorbitanmonooleate and the high molecular weight adducts of ethylene oxide witha hydrophobic base, formed by the condensation of propylene oxide withpropylene glycol.

The pharmaceutical compositions may be in the form of sterile injectableaqueous suspensions. Such suspensions may be formulated according toknown methods using suitable dispersing or wetting agents and suspendingagents such as, for example, sodium carboxymethylcellulose,methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate,polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing orwetting agents which may be a naturally occurring phosphatide such aslecithin, a condensation product of an alkylene oxide with a fatty acid,for example, polyoxyethylene stearate, a condensation product ofethylene oxide with a long chain aliphatic alcohol, for example,heptadeca-ethyleneoxycetanol, a condensation product of ethylene oxidewith a partial ester derived form a fatty acid and a hexitol such aspolyoxyethylene sorbitol monooleate, or a condensation product of anethylene oxide with a partial ester derived from a fatty acid and ahexitol anhydride, for example polyoxyethylene sorbitan monooleate.

The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, Diluents and solvents that may be employed are, for example,water, Ringer's solution, isotonic sodium chloride solutions andisotonic glucose solutions. In addition, sterile fixed oils areconventionally employed as solvents or suspending media. For thispurpose, any bland, fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid can be usedin the preparation of injectables.

A compositions of the invention may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritationexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such material is, for example, cocoa butter and polyethyleneglycol.

Controlled release formulations for parenteral administration includeliposomal, polymeric microsphere and polymeric gel formulations whichare known in the art.

The pharmaceutical compositions of this invention may also be in theform of a solid dispersion. The solid dispersion may be a solidsolution, glass solution, glass suspension, amorphous precipitation in acrystalline carrier, eutectic or monotecic, compound or complexformation and combinations thereof.

An aspect of the invention of particular interest is a pharmaceuticalcomposition comprising a solid dispersion, wherein the matrix comprisesa pharmaceutically acceptable polymer, such as polyvinylpyrrolidone,vinylpyrrolidone/vinylacetate copolymer, polyalkylene glycol (i.e.polyethylene glycol), hydroxyalkyl cellulose (i.e. hydroxypropylcellulose), hydroxyalkyl methyl cellulose (i.e. hydroxypropyl methylcellulose), carboxymethyl cellulose, sodium carboxymethyl cellulose,ethyl cellulose, polymethacrylates, polyvinyl alcohol, polyvinylacetate, vinyl alcohol/vinyl acetate copolymer, polyglycolizedglycerides, xanthan gum, carrageenan, chitosan, chitin, polydextrin,dextrin, starch and proteins.

Another aspect of the invention is a pharmaceutical compositioncomprising a solid dispersion, wherein the matrix comprises a sugarand/or sugar alcohol and/or cyclodextrin, for example sucrose, lactose,fructose, maltose, raffinose, sorbitol, lactitol, mannitol, maltitol,erythritol, inositol, trehalose, isomalt, inulin, maltodextrin,β-cyclodextrin, hydroxypropyl-β-cyclodextrin or sulfobutyl ethercyclodextrin.

Additional suitable carriers that are useful in the formation of thematrix of the solid dispersion include, but are not limited to alcohols,organic acids, organic bases, amino acids, phospholipids, waxes, salts,fatty acid esters, polyoxyethylene sorbitan fatty acid esters, and urea.

The solid dispersion of regorafenib in the matrix may contain certainadditional pharmaceutical acceptable ingredients, such as surfactants,fillers, disintegrants, recrystallization inhibitors, plasticizers,defoamers, antioxidants, detackifier, pH-modifiers, glidants andlubricants.

The solid dispersion of the invention is prepared according to methodsknown to the art for the manufacture of solid dispersions, such asfusion/melt technology, hot melt extrusion, solvent evaporation (i.e.freeze drying, spray drying or layering of powders of granules),coprecipitation, supercritical fluid technology and electrostaticspinning method.

The compositions of the invention can also contain other conventionalpharmaceutically acceptable compounding ingredients, generally referredto as carriers or diluents, as necessary or desired.

Conventional procedures for preparing such compositions in appropriatedosage forms can be utilized.

Commonly used pharmaceutical ingredients which can be used asappropriate to formulate the composition for its intended route ofadministration include:

-   -   acidifying agents (examples include but are not limited to        acetic acid, citric acid, fumaric acid, hydrochloric acid,        nitric acid);    -   alkalinizing agents (examples include but are not limited to        ammonia solution, ammonium carbonate, diethanolamine,        monoethanolamine, potassium hydroxide, sodium borate, sodium        carbonate, sodium hydroxide, triethanolamine, trolamine);    -   adsorbents (examples include but are not limited to powdered        cellulose and activated charcoal);    -   aerosol propellants (examples include but are not limited to        carbon dioxide, CCl₂F₂, F₂ClC—CClF₂ and CClF₃)    -   air displacement agents (examples include but are not limited to        nitrogen and argon);    -   antifungal preservatives (examples include but are not limited        to benzoic acid, butylparaben, ethylparaben, methylparaben,        propylparaben, sodium benzoate);    -   antimicrobial preservatives (examples include but are not        limited to benzalkonium chloride, benzethonium chloride, benzyl        alcohol, cetylpyridinium chloride, chlorobutanol, phenol,        phenylethyl alcohol, phenylmercuric nitrate and thimerosal);    -   antioxidants (examples include but are not limited to ascorbic        acid, ascorbyl palmitate, butylated hydroxyanisole, butylated        hydroxytoluene, hypophosphorus acid, monothioglycerol, propyl        gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde        sulfoxylate, sodium metabisulfite);    -   binding materials (examples include but are not limited to block        polymers, natural and synthetic rubber, polyacrylates,        polyurethanes, silicones, polysiloxanes and styrene-butadiene        copolymers);    -   buffering agents (examples include but are not limited to        potassium metaphosphate, dipotassium phosphate, sodium acetate,        sodium citrate anhydrous and sodium citrate dihydrate)    -   carrying agents (examples include but are not limited to acacia        syrup, aromatic syrup, aromatic elixir, cherry syrup, cocoa        syrup, orange syrup, syrup, corn oil, mineral oil, peanut oil,        sesame oil, bacteriostatic sodium chloride injection and        bacteriostatic water for injection)    -   chelating agents (examples include but are not limited to        edetate disodium and edetic acid)    -   colorants (examples include but are not limited to FD&C Red No.        3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C        Green No. 5, D&C Orange No. 5, D&C Red No. 8, caramel and ferric        oxide red);    -   clarifying agents (examples include but are not limited to        bentonite);    -   emulsifying agents (examples include but are not limited to        acacia, cetomacrogol, cetyl alcohol, glyceryl monostearate,        lecithin, sorbitan monooleate, polyoxyethylene 50 monostearate);    -   encapsulating agents (examples include but are not limited to        gelatin and cellulose acetate phthalate)    -   flavorants (examples include but are not limited to anise oil,        cinnamon oil, cocoa, menthol, orange oil, peppermint oil and        vanillin);    -   humectants (examples include but are not limited to glycerol,        propylene glycol and sorbitol);    -   levigating agents (examples include but are not limited to        mineral oil and glycerin);    -   oils (examples include but are not limited to arachis oil,        mineral oil, olive oil, peanut oil, sesame oil and vegetable        oil);    -   ointment bases (examples include but are not limited to lanolin,        hydrophilic ointment, polyethylene glycol ointment, petrolatum,        hydrophilic petrolatum, white ointment, yellow ointment, and        rose water ointment);    -   penetration enhancers (transdermal delivery) (examples include        but are not limited to monohydroxy or polyhydroxy alcohols,        mono- or polyvalent alcohols, saturated or unsaturated fatty        alcohols, saturated or unsaturated fatty esters, saturated or        unsaturated dicarboxylic acids, essential oils, phosphatidyl        derivatives, cephalin, terpenes, amides, ethers, ketones and        ureas)    -   plasticizers (examples include but are not limited to diethyl        phthalate and glycerol);    -   solvents (examples include but are not limited to ethanol, corn        oil, cottonseed oil, glycerol, isopropanol, mineral oil, oleic        acid, peanut oil, purified water, water for injection, sterile        water for injection and sterile water for irrigation);    -   stiffening agents (examples include but are not limited to cetyl        alcohol, cetyl esters wax, microcrystalline wax, paraffin,        stearyl alcohol, white wax and yellow wax);    -   suppository bases (examples include but are not limited to cocoa        butter and polyethylene glycols (mixtures));    -   surfactants (examples include but are not limited to        benzalkonium chloride, nonoxynol 10, oxtoxynol 9, polysorbate        80, sodium lauryl sulfate and sorbitan mono-palmitate);    -   suspending agents (examples include but are not limited to agar,        bentonite, carbomers, carboxymethylcellulose sodium,        hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl        methylcellulose, kaolin, methylcellulose, tragacanth and        veegum);    -   sweetening agents (examples include but are not limited to        aspartame, dextrose, glycerol, mannitol, propylene glycol,        saccharin sodium, sorbitol and sucrose);    -   tablet anti-adherents (examples include but are not limited to        magnesium stearate and talc);    -   tablet binders (examples include but are not limited to acacia,        alginic acid, carboxymethylcellulose sodium, compressible sugar,        ethylcellulose, gelatin, liquid glucose, methylcellulose,        non-crosslinked polyvinyl pyrrolidone, and pregelatinized        starch);    -   tablet and capsule diluents (examples include but are not        limited to dibasic calcium phosphate, kaolin, lactose, mannitol,        microcrystalline cellulose, powdered cellulose, precipitated        calcium carbonate, sodium carbonate, sodium phosphate, sorbitol        and starch);    -   tablet coating agents (examples include but are not limited to        liquid glucose, hydroxyethyl cellulose, hydroxypropyl cellulose,        hydroxypropyl methylcellulose, methylcellulose, ethylcellulose,        cellulose acetate phthalate and shellac);    -   tablet direct compression excipients (examples include but are        not limited to dibasic calcium phosphate);    -   tablet disintegrants (examples include but are not limited to        alginic acid, carboxymethylcellulose calcium, microcrystalline        cellulose, polacrillin potassium, cross-linked        polyvinylpyrrolidone, sodium alginate, sodium starch glycollate        and starch);    -   tablet glidants (examples include but are not limited to        colloidal silica, corn starch and talc);    -   tablet lubricants (examples include but are not limited to        calcium stearate, magnesium stearate, mineral oil, stearic acid        and zinc stearate);    -   tablet/capsule opaquants (examples include but are not limited        to titanium dioxide);    -   tablet polishing agents (examples include but are not limited to        carnauba wax and white wax);    -   thickening agents (examples include but are not limited to        beeswax, cetyl alcohol and paraffin);    -   tonicity agents (examples include but are not limited to        dextrose and sodium chloride);    -   viscosity increasing agents (examples include but are not        limited to alginic acid, bentonite, carbomers,        carboxymethylcellulose sodium, methylcellulose, polyvinyl        pyrrolidone, sodium alginate and tragacanth); and    -   wetting agents (examples include but are not limited to        heptadecaethylene oxycetanol, lecithin, sorbitol monooleate,        polyoxyethylene sorbitol monooleate, and polyoxyethylene        stearate).

It is believed that one skilled in the art, utilizing the precedinginformation, can utilize the present invention to its fullest extent.

What is claimed is:
 1. A method of treating a hyper-proliferativedisorder in a human subject in need thereof comprising orallyadministering an effective amount of a pharmaceutical combinationcomprising regorafenib and acetylsalicylic acid, or a hydrate, solvate,or pharmaceutically acceptable salt thereof, or a polymorph thereof,wherein the hyper-proliferative disorder is colorectal cancer, whereinthe regorafenib is administered in a dose in an amount of 10 to 100 mgand the acetylsalicylic acid is administered in a dose in an amount of50 to 100 mg.
 2. The method of claim 1, wherein regorafenib andacetylsalicylic acid are administered daily for three weeks and in afourth week only regorafenib is administered daily.
 3. The method ofclaim 1, wherein the regorafenib and acetylsalicylic acid, or a hydrate,solvate, or pharmaceutically acceptable salt thereof, or a polymorphthereof are administered in separate dosage forms simultaneously orsequentially.
 4. The method of claim 1, wherein the total daily dose ofregorafenib administered is from 80 to 320 mg/day and the total dailydose of acetylsalicylic acid administered is from 70 to 350 mg/day.